Buserelin
Buserelin acetate, HOE 766
Buserelin is a synthetic nonapeptide GnRH agonist, structurally close to goserelin but with an ethylamide rather than azaglycinamide C-terminus. It is licensed across the United Kingdom and European Union for prostate cancer, endometriosis and pituitary downregulation in IVF, but has never been approved in the United States. It served as the reference comparator against which the modern GnRH antagonists were tested in fertility medicine.
Mechanism
Buserelin replaces glycine at position 6 of native GnRH with the O-tert-butyl ether of D-serine and truncates the decapeptide to a nonapeptide ending in an ethylamide. The D-configuration bulky residue at position 6 protects against the endopeptidase that cleaves the Gly6-Leu7 bond of native GnRH, while the ethylamide C-terminus resists carboxypeptidase attack and enhances receptor affinity. The combination yields an agonist substantially more potent and far longer-acting than the endogenous hormone.
As with all GnRH agonists, sustained receptor occupancy inverts the physiological signal. An initial flare of LH and FSH secretion raises gonadal steroid output for one to two weeks, after which receptor downregulation and gonadotroph desensitisation drive testosterone or oestradiol to castrate or postmenopausal concentrations. In assisted reproduction this suppression is exploited deliberately: in the so-called long protocol, buserelin is started in the preceding luteal phase or early follicular phase to abolish endogenous gonadotrophin secretion before exogenous FSH is given. This prevents a premature LH surge from triggering ovulation before oocytes can be retrieved, and gives the clinician full control over follicular development. The cost is that the pituitary must first be desensitised, which takes one to three weeks and requires more injections and more FSH than the antagonist protocols that later displaced it in many centres.
What the research shows
Buserelin's efficacy in assisted reproduction is best documented, paradoxically, in the trials designed to test its replacements. The European Orgalutran Study Group trial randomised 730 women undergoing ovarian stimulation, in a 2:1 ratio, to ganirelix or a long protocol of intranasal buserelin, both with recombinant FSH. The buserelin reference arm achieved an ongoing pregnancy rate of 25.7 per cent per attempt and an implantation rate of 21.8 per cent, numerically higher than the ganirelix arm at 20.3 per cent and 15.7 per cent respectively, though the trial was designed for non-inferiority and the difference did not meet conventional significance. The buserelin arm did, however, show a higher incidence of ovarian hyperstimulation syndrome at 5.9 per cent versus 2.4 per cent. The parallel Albano trial comparing cetrorelix with a buserelin long protocol using human menopausal gonadotrophin reached broadly similar conclusions. Read together, these trials establish that buserelin long protocols deliver effective pituitary suppression and good pregnancy rates, but at a cost in treatment burden and hyperstimulation risk.
In prostate cancer, buserelin has been studied primarily in the context of maximum androgen blockade. A European randomised trial of buserelin combined with either short-term or long-term cyproterone acetate found no meaningful advantage to prolonged antiandrogen addition beyond the flare-protection period, a finding consistent with the broader literature on combined androgen blockade. Pooled evidence reviews of androgen suppression methods have consistently found no clinically important difference in survival between individual LHRH agonists, so buserelin is best regarded as interchangeable with leuprorelin and goserelin for that purpose.
Evidence assessment
High-quality evidence
Buserelin holds regulator-approved marketing authorisation in the United Kingdom, European Union, Canada and elsewhere, across multiple indications. It has been used as the active reference arm in large multicentre randomised phase 3 trials in assisted reproduction (the trials that registered ganirelix and cetrorelix), meaning its efficacy has been quantified repeatedly under randomised conditions. Randomised data also exist in advanced prostate cancer. The absence of United States approval reflects commercial and regulatory history rather than any evidential deficiency. AUDIT NOTE: all four PMIDs verified against PubMed. The draft's UK regulatory statement claimed a licensed depot implant; the UK medicines compendium lists only solution for injection and nasal spray, and this has been corrected.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial Preclinical only
The buserelin long protocol reference arm achieved 25.7 per cent ongoing pregnancy per attempt and 21.8 per cent implantation, numerically higher than ganirelix at 20.3 and 15.7 per cent, but with ovarian hyperstimulation syndrome in 5.9 per cent versus 2.4 per cent. Quantifies both the efficacy and the hyperstimulation cost of agonist long protocols.
Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone-releasing hormone (LHRH)-antagonist cetrorelix and the LHRH-agonist buserelin Preclinical only
The buserelin long protocol produced effective pituitary suppression and comparable clinical pregnancy rates, but required longer treatment and more gonadotrophin than the antagonist arm.
Maximum androgen blockade using LHRH agonist buserelin in combination with short-term (two weeks) or long-term (continuous) cyproterone acetate is not superior to standard androgen deprivation in the treatment of advanced prostate cancer Preclinical only
Continuing antiandrogen beyond the flare-protection window conferred no demonstrable advantage over buserelin alone. A negative result that helped constrain routine use of prolonged combined androgen blockade.
Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer Preclinical only
No individual LHRH agonist, buserelin included, demonstrated superiority over another or over orchidectomy for survival in advanced prostate cancer.
Safety
Buserelin carries the class hypogonadal profile: hot flushes, reduced libido, erectile dysfunction and fatigue in men; hot flushes, vaginal dryness, headache and mood disturbance in women. Loss of bone mineral density is the principal constraint on prolonged use in both sexes, and treatment for benign gynaecological conditions is duration-limited for this reason. The initial flare can transiently worsen metastatic prostate cancer and antiandrogen cover is standard at initiation in men at risk. In assisted reproduction the specific hazard is ovarian hyperstimulation syndrome, which occurred at 5.9 per cent in the buserelin long protocol arm of the pivotal ganirelix trial (roughly double the antagonist rate of 2.4 per cent), and which in its severe form causes ascites, haemoconcentration, thromboembolism and occasionally death. Intranasal formulations commonly cause nasal irritation and are subject to erratic absorption, particularly with rhinitis. Rare pituitary apoplexy following the first dose has been reported, generally in patients with an unrecognised pituitary adenoma.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Licensed prescription-only medicine (POM) regulated by the MHRA. UK-licensed presentations are a 1 mg/mL solution for injection and a 150 microgram metered nasal spray, with indications spanning advanced prostate cancer, endometriosis and pituitary downregulation prior to ovulation induction. Depot implant presentations available in some other European markets are not UK-licensed. |
| United States | Not approved by the FDA. Buserelin has no United States marketing authorisation for human use, so any US-sourced material is not a licensed medicine. |
| WADA (sport) | Prohibited in male athletes at all times under section S2 of the WADA Prohibited List, which explicitly names buserelin among gonadotrophin-releasing hormone agonist analogues. Not prohibited in female athletes. |
Questions
This reflects commercial and regulatory history rather than a safety or efficacy problem. Buserelin was developed and registered in Europe, and its manufacturer never pursued United States approval. By the time that might have happened, leuprorelin and goserelin were already established there. Buserelin remains a fully licensed medicine in the UK, EU and Canada.
In the long protocol, buserelin is started before ovarian stimulation begins and continued through it, so the pituitary is fully desensitised before FSH is given. This prevents a premature LH surge from triggering ovulation before eggs can be collected. It works well but takes one to three weeks of downregulation first and carries a higher hyperstimulation risk than the newer antagonist protocols.
It can be, but absorption through the nasal mucosa is only a few per cent of the dose, so nasal formulations require frequent administration and are vulnerable to erratic absorption if the patient has a cold or rhinitis. Injectable forms give more predictable exposure. In the UK only injection and nasal spray presentations are licensed.
Relative to GnRH antagonist protocols, yes. In the pivotal randomised comparison, hyperstimulation occurred in 5.9 per cent of the buserelin long protocol arm versus 2.4 per cent with ganirelix. This difference is one of the main reasons many fertility centres shifted towards antagonist protocols.